Randomized Controlled Trial

. 2021 Feb;89(2):304-314.

doi: 10.1002/ana.25956. Epub 2020 Nov 27.

Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial

Katarzyna Kotulska¹, David J Kwiatkowski², Paolo Curatolo³, Bernhard Weschke⁴, Kate Riney^{5

6}, Floor Jansen⁷, Martha Feucht⁸, Pavel Krsek⁹, Rima Nabbout¹⁰, Anna C Jansen^{11

12}, Konrad Wojdan^{13

14}, Kamil Sijko^{1

13}, Jagoda Głowacka-Walas^{1

15}, Julita Borkowska¹, Krzysztof Sadowski¹, Dorota Domańska-Pakieła¹, Romina Moavero¹⁶, Christoph Hertzberg⁴, Hanna Hulshof⁷, Theresa Scholl⁸, Barbora Benova⁹, Eleonora Aronica¹⁷, Jessie de Ridder¹⁸, Lieven Lagae¹⁸, Sergiusz Jóźwiak^{1

19}; EPISTOP Investigators

Collaborators, Affiliations

Collaborators

EPISTOP Investigators:
J Anink, E Aronica, B Benova, A Benvenuto, M Blazejczyk, A Bongaerts, J Borkowska, D Breuillard, D Chmielewski, P Curatolo, M Dabrowska, D Domańska-Pakieła, M Feucht, K Giannikou, J Głowacka-Walas, L Hamieh, A Harȩza, Ch Hertzberg, H Hulshof, F Huschner, A Iyer, A Jansen, F Jansen, B Janssen, J Jaworski, S Jùźwiak, M Kaczorowska-Frontczak, K Kotulska, P Krsek, D Kwiatkowski, L Lagae, K Lehmann, A Leusman, N Maćkowiak, J Mills, R Moavero, A Muelebner, R Nabbout, J de Ridder, K Riney, K Sadowski, S Samueli, C Scheldeman, T Scholl, A Sciuto, K Sijko, M Słowińska, A Tempes, J van Scheppingen, B Verhelle, J Vervisch, M Urbańska, B Weschke, K Wojdan

Affiliations

¹ Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland.
² Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³ Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy.
⁴ Department of Child Neurology, Charité University Medicine Berlin, Berlin, Germany.
⁵ Neurosciences Unit, Queensland Children's Hospital, South Brisbane, QLD, Australia.
⁶ School of Medicine, University of Queensland, St Lucia, QLD, Australia.
⁷ Department of Child Neurology, Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands.
⁸ Department of Pediatrics, University Hospital Vienna, Vienna, Austria.
⁹ Motol University Hospital, Charles University, Prague 5, Czech Republic.
¹⁰ Department of Pediatric Neurology, Reference Centre for Rare Epilepsies, Necker- Enfants Malades Hospital, University Paris Descartes, Imagine Institute, Paris, France.
¹¹ Pediatric Neurology Unit-UZ Brussel, Brussels, Belgium.
¹² Neurogenetics Research Group, Vrije Universiteit Brussel, Brussels, Belgium.
¹³ Transition Technologies, Warsaw, Poland.
¹⁴ Warsaw University of Technology, Institute of Heat Engineering, Warsaw, Poland.
¹⁵ Warsaw University of Technology, The Faculty of Electronics and Information Technology, Warsaw, Poland.
¹⁶ Child Neurology Unit, Neuroscience and Neurorehabilitation Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁷ Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, The Netherlands.
¹⁸ Department of Development and Regeneration-Section Pediatric Neurology, University Hospitals KU Leuven, Leuven, Belgium.
¹⁹ Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland.

PMID: 33180985
PMCID: PMC7898885
DOI: 10.1002/ana.25956

Randomized Controlled Trial

Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial

Katarzyna Kotulska et al. Ann Neurol. 2021 Feb.

. 2021 Feb;89(2):304-314.

doi: 10.1002/ana.25956. Epub 2020 Nov 27.

Authors

Collaborators

EPISTOP Investigators:
J Anink, E Aronica, B Benova, A Benvenuto, M Blazejczyk, A Bongaerts, J Borkowska, D Breuillard, D Chmielewski, P Curatolo, M Dabrowska, D Domańska-Pakieła, M Feucht, K Giannikou, J Głowacka-Walas, L Hamieh, A Harȩza, Ch Hertzberg, H Hulshof, F Huschner, A Iyer, A Jansen, F Jansen, B Janssen, J Jaworski, S Jùźwiak, M Kaczorowska-Frontczak, K Kotulska, P Krsek, D Kwiatkowski, L Lagae, K Lehmann, A Leusman, N Maćkowiak, J Mills, R Moavero, A Muelebner, R Nabbout, J de Ridder, K Riney, K Sadowski, S Samueli, C Scheldeman, T Scholl, A Sciuto, K Sijko, M Słowińska, A Tempes, J van Scheppingen, B Verhelle, J Vervisch, M Urbańska, B Weschke, K Wojdan

Affiliations

¹ Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland.
² Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³ Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy.
⁴ Department of Child Neurology, Charité University Medicine Berlin, Berlin, Germany.
⁵ Neurosciences Unit, Queensland Children's Hospital, South Brisbane, QLD, Australia.
⁶ School of Medicine, University of Queensland, St Lucia, QLD, Australia.
⁷ Department of Child Neurology, Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands.
⁸ Department of Pediatrics, University Hospital Vienna, Vienna, Austria.
⁹ Motol University Hospital, Charles University, Prague 5, Czech Republic.
¹⁰ Department of Pediatric Neurology, Reference Centre for Rare Epilepsies, Necker- Enfants Malades Hospital, University Paris Descartes, Imagine Institute, Paris, France.
¹¹ Pediatric Neurology Unit-UZ Brussel, Brussels, Belgium.
¹² Neurogenetics Research Group, Vrije Universiteit Brussel, Brussels, Belgium.
¹³ Transition Technologies, Warsaw, Poland.
¹⁴ Warsaw University of Technology, Institute of Heat Engineering, Warsaw, Poland.
¹⁵ Warsaw University of Technology, The Faculty of Electronics and Information Technology, Warsaw, Poland.
¹⁶ Child Neurology Unit, Neuroscience and Neurorehabilitation Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁷ Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, The Netherlands.
¹⁸ Department of Development and Regeneration-Section Pediatric Neurology, University Hospitals KU Leuven, Leuven, Belgium.
¹⁹ Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland.

PMID: 33180985
PMCID: PMC7898885
DOI: 10.1002/ana.25956

Abstract

Objective: Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants.

Methods: In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open-label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure.

Results: In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty-seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223-535) vs 124 days (95% CI = 33-149); OLT: 426 days (95% CI = 258-628) vs 106 days (95% CI = 11-149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug-resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted.

Interpretation: Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304-314.

PubMed Disclaimer

Conflict of interest statement

Nothing to report.

Figures

**FIGURE 1**
EPISTOP subject flow chart. EEG = electroencephalogram, EA = epileptiform activity.

**FIGURE 2**
Time (in days) to clinical epileptic seizures in EPISTOP patients receiving preventive or conventional antiepileptic treatment in the randomized controlled trial and open‐label trial. Probability values are from the log‐rank test.

See this image and copyright information in PMC

References

1. Salussolia CL, Klonowska K, Kwiatkowski DJ, Sahin M. Genetic etiologies, diagnosis, and treatment of tuberous sclerosis complex. Annu Rev Genomics Hum Genet 2019;31:217–240. - PubMed
1. Dragoumi P, O'Callaghan F, Zafeiriou DI. Diagnosis of tuberous sclerosis complex in the fetus. Eur J Paediatr Neurol 2018;22:1027–1034. - PubMed
1. Overwater IE, Bindels‐de Heus K, Rietman AB, et al. Epilepsy in children with tuberous sclerosis complex: chance of remission and response to antiepileptic drugs. Epilepsia 2015;56:1239–1245. - PubMed
1. Nabbout R, Belousova E, Benedik MP, et al. Epilepsy in tuberous sclerosis complex: findings from the TOSCA study. Epilepsia Open 2019;4:73–84. - PMC - PubMed
1. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE Official Report: a practical clinical definition of epilepsy. Epilepsia 2014;55:475–482. - PubMed

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Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial

Collaborators

Affiliations

Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical